N,N′-Bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxy-1-oxopropyl]-amino]-2,4,6-triiodo-1,3-benzendicarboxamide (see the formula below), generally known as Iopamidol (The Merck Index, XIII Ed., 2001, Nr. 5073), is a compound broadly used for diagnostic methodologies:

Several processes are known in literature for the preparation of Iopamidol, e.g. starting from 5-nitroisophtalic acid, contemplating the use of many reagents and solvent systems, the optional isolation of the synthetic intermediates and the purification of the final product. The 5-nitroisophtalic acid, as a possible starting material, is suitably reduced to the corresponding amine derivative, e.g. by catalytic hydrogenation, and it is subsequently iodinated on the phenyl ring so to form the corresponding 2,4,6-triiodine derivative.
This latter, e.g. in the presence of thionyl chloride, is then converted into the corresponding 5-amino-2,4,6-triiodoisophthalic acid dichloride, (see, e.g. WO 96/037458, WO96/037459, WO96/016927 and WO96/036590).
The process for the preparation of Iopamidol starting from 5-amino-2,4,6-triiodoisophthalic acid dichloride, comprising possible variations thereof, may be described according to the following synthetic scheme (see, e.g., WO 96/037460, U.S. Pat. No. 5,362,905, WO 97/047590, WO 98/24757, WO 98/028259 and WO 99/058494):

The 5-amino-2,4,6-triiodoisophthalic acid dichloride (I) is converted to the corresponding compound of formula (II) in the presence of (S)-[2-(acetyloxy)]propionic acid chloride. The intermediate of formula (II) thus prepared, is then converted in the acetyl-iopamidol of formula (III) in the presence of 2-amino-1,3-propandiol. Finally, the hydrolysis of the compound of formula (III) and the subsequent purification step, allow for the isolation of Iopamidol (formula (IV).
The use of suitable bases in the condensation reaction between 2-amino-1,3-propandiol and compound (II) is known in the art where, particularly, a tertiary amine is added to the reaction system before the addition of 2-amino-1,3-propandiol (see, e.g., WO 98/24757).
Such addition results to be remarkably advantageous as it enables for the neutralization of the acid being formed during the reaction between compound (II) and 2-amino-1,3-propandiol, avoiding by that, the possible and undesired salification of said acid with the 2-amino-1,3-propandiol.
Among the possible tertiary amines which may be employed, aliphatic tertiary amines, in particular, have been reported, such as, for instance, triethylamine, tripropylamine, tributylamine and diisopropylethylamine.
As disclosed in the aforementioned patent applications, the use of inorganic bases in lieu of the tertiary amines would not result as favourable as the use of a tertiary amine, since it would require particularly long reaction times, due to the insolubility of the bases in the organic reaction solvent, such as e.g. dimethylacetamide (DMA).
Further, the salts resulting from the reaction of the excess of (S)-[2-(acetyloxy)]propionic acid chloride in the reaction system would likely be filtered together with the product, and therefore they might help in compromising the overall yield and the impurities profile of the final product.
To our knowledge, the use of specific bases in the condensation reaction between an aminoalcohol and an appropriate isopthalic acid dichloride, has been described in literature even for the preparation of other non ionic iodinated contrast agents.
We refer, for example, to a process for the preparation of ioversol (The Merck Index, XIII Ed., 2001, Ne. 5085) by reacting 3-amino-1,2-propandiol with 5-acetoxyacetamido-2,4,6-triiodoisopthalic acid dichloride, in the presence of bases and aprotic dipolar organic solvents, particularly dimethylacetamide (DMA) dimethylformamide (DMF) or dimethylsulfoxide (DMSO).
However, the only experimental evidences noticed about the above condensation reaction, whenever said reaction is carried out in the presence of inorganic bases as described, for instance, in the Indian patent IN 187816, contemplate the use of sodium hydroxide in the presence of isopropanol as possible solvent or, alternatively, the employment of potassium carbonate in DMF.
Surprisingly, we have now found that specific inorganic bases, such as, for example, alkaline or rare earth metals oxides or hydroxides, in the reaction conditions as herein set forth, may be conveniently employed in the process for the preparation of iopamidol. Such a process allows at the same time for the neutralization of the acid as formed during the afore mentioned condensation reaction and for the use of mild conditions in the selected solvent. Said process, further, enables for the preparation of iopamidol in high yields and with a high degree of purity.
In this respect, as it is for the others contrast agents being used in the diagnostic field, it is of major importance also for iopamidol that the raw material may be obtained with a high degree of purity so to be able to optimize, even with remarkable results, the purification steps as required for the achievement of the final product, being the latter intended for the administration and therefore in conformity with the limits and the specifications according to Pharmacopoeia.
Among the known impurities related to iopamidol, it is worth noting, in particular, the compound N′-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[[(2S)-2-hydroxypropanoyl]amino]-2,4,6-triodo-N,N-dimethylbenzene-1,3-dicaroxamide, which structure is reported below:

The above compound, hereinafter indicated as F-impurity, is within the list of possible side-products generated from the synthesis of iopamidol (e.g. see European Pharmacopoeia 6.0 Ed. 01/2008:1115).
Advantageously, the process of the present invention enables for the preparation of iopamidol with a particularly low amount of F-impurity as well as others side-products, whilst using inorganic bases. All the above allows for the removal of such side products by ordinary purification steps, so to collect the final product within the imposed limitations, as previously indicated